Compositions and methods for treating centrally mediated nausea and vomiting

ABSTRACT

Provided are methods for treating nausea and vomiting in patients undergoing chemotherapy, radiotherapy, or surgery, comprising the co-administration of netupitant, palonosetron and dexamethasone.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/IB10/03106, filed Nov. 18, 2010; which claims priority to U.S.Provisional Application No. 61/262,470, filed Nov. 18, 2009; and U.S.Provisional Application No. 61/382,709, filed Sep. 14, 2010. ApplicationNos. 61/262,470 and 61/382,709 and PCT Application No. PCT/IB10/03106are hereby incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the use of centrally acting NK₁antagonists to treat nausea and vomiting, particular nausea and vomitinginduced by highly emetogenic chemotherapy, and to the treatment of suchnausea and vomiting over multiple consecutive days. The presentinvention also relates to combined oral dosage forms of palonosetron andnetupitant.

BACKGROUND OF THE INVENTION

With the development of the 5-HT₃ antagonist in the early 1990s, thereemerged new strategies in the medical community to better control nauseaand vomiting caused by various medical procedures, includingchemotherapy (CINV), surgery (PONV), and radiation therapy (RINV). Whenadded to steroids such as dexamethasone, several 5-HT₃ antagonists havebeen demonstrated to significantly improve the standard of life forpatients undergoing emetogenic medical procedures. Examples of 5-HT₃antagonists include ondansetron, marketed by GlaxoSmithKline, andpalonosetron, developed by Helsinn Healthcare.

Palonosetron hydrochloride has recently emerged as a highly efficaciousanti-nauseant and anti-emetic agent. See PCT publications WO 2004/045615and 2004/073714 from Helsinn Healthcare. Palonosetron hydrochloride issold in the United States as a sterile injectable liquid under theALOXI® brand, in sterile unit dose vials containing 0.075 or 0.25 mg. ofpalonosetron hydrochloride. Palonosetron hydrochloride also is also soldas an orally administered soft-gel dosage form containing 0.5 mg. ofpalonosetron hydrochloride.

The official chemical name for palonosetron hydrochloride is(3aS)-2-[(S)-1-Azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hberiz[de]isoquinolinehydrochloride (CAS No. 119904-90-4); its empirical formula isC₁₉H₂₄N₂O.HCl, and its molecular weight is 332.87. The compound isrepresented by the following chemical structure:

Methods of synthesizing palonosetron are described in U.S. Pat. Nos.5,202,333 and 5,510,486. Pharmaceutically acceptably dosage forms aredescribed in PCT publications WO 2004/067005 and WO 2008/049552 fromHelsinn Healthcare.

NK₁ antagonists have also recently emerged as a tool for combatingnausea and vomiting from emetogenic medical procedures. Most recently,aprepitant was approved by the Food and Drug Administration (“FDA”) foruse in combination with other anti-emetic agents for the prevention ofnausea and vomiting from moderately and highly emetogenic chemotherapy.However, it quickly became apparent that aprepitant's effect was limitedprincipally to vomiting—not nausea—and that aprepitant did not provideas much benefit during the acute phase of CINV. When tested againstnausea in humans, aprepitant was unable to induce a significantreduction in the incidence or severity of nausea following moderately orhighly emetogenic chemotherapy when compared to a 5-HT₃ antagonistalone. See FDA Approved Labeling for Emend®. Thus, while aprepitant isapproved by FDA for the prevention of nausea and vomiting in humans,this indication is somewhat misleading because aprepitant did not reducenausea in the clinical trials preformed for aprepitant more than nauseacontrolled by the other components of the anti-emetic regimen. Inaddition, the results reported in Grunberg et al., SUPPORT CANCER CARE(2009) 17:589-594, from a combined treatment of aprepitant andpalonosetron, were far from promising.

Merck & Co. markets aprepitant, as EMEND® in the United States. Theproduct is approved in a capsule dosage form, and is marketed for theprevention of CINV (acute and delayed) in combination with otheranti-emetic agents such as ondansetron and metoclopramide. The productreportedly has a terminal half-life of from 9 to 13 hours. Whileaprepitant has demonstrated some effect against nausea, its effects havebeen inconsistent. Casopitant is another NK₁ antagonist that has beentested against nausea and vomiting in humans. A clinical study ofcasopitant is discussed in Therapeutics and Clinical Risk Management2009:5 pp 375-384 to Ruhlmann et al. and Drug Metabolism andDisposition, vol. 37, No. 8, 2009, pp. 1635-1645 to Pellegatti et al. Asreported by Ruhlmann et al. in THERAPEUTICS AND CLINICAL RISKMANAGEMENT, 2009:5 375-384, casopitant had no statistically significanteffect against nausea when administered in response to moderatelyemetogenic chemotherapy, and even induced nausea as a side effect.Casopitant has the formula(2R,4S)-4-(4-acetytlpiperazin-1-yl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide,and the below chemical structure:

Netupitant is another selective NK₁ receptor antagonist underdevelopment by Helsinn Healthcare, having the formula2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide,or Benzeneacetamide,N,α,α-trimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3,5-bis(trifluoromethyl)-,and the below chemical structure:

Methods of synthesizing and formulating netupitant and its prodrugs aredescribed in U.S. Pat. Nos. 6,297,375, 6,719,996 and 6,593,472 toHoffmann La Roche.

Other representative NK₁ antagonists include ZD4974 (developed byAstraZeneca), CGP49823 (developed by Ciba-Geigy), Lanepitant andLY686017 (developed by Eli Lilly), FK888 (developed by Fujisawa),Vofopitant, Vestipitant and Orvepitant (developed by GlaxoSmithKline),Befetupitant (developed by Hoffmann-La Roche), R116031 (developed byJanssen), L-733060 and L-736281 (developed by Merck), TKA731, NKP608 andDNK333 (developed by Novartis), CP-96345, CP-99994, CP-122721, CJ-17493,CJ-11974 and CJ-11972 (developed by Pfizer), RP67580 and Dapitant(developed by Rhone-Poulenc Rorer), Nolpitantium and SSR240600(developed by Sanofi-Aventis), SCH388714 and Rolapitant (developed bySchering-Plough), TAK637 (developed by Takeda), HSP117 (developed byHisamitsu), KRP103 (developed by Kyorin Pharm) and SLV317 (developed bySolvay). Chemical structures of the above-mentioned NK₁ antagonists areshown below and discussion of those compounds as well as other NK₁antagonists is present in Expert Opin. Ther. Patents (2010) 20(8), pp1019-1045 by Huang et al.

The background of U.S. Pat. No. 6,297,375 suggests that NK₁ antagonistsare useful for treating a variety of conditions in which substance P(the natural ligand for the NK₁ receptor) is active. These conditionsinclude depression, pain (especially pain resulting from inflammatoryconditions such as migraine, rheumatoid arthritis, asthma, andinflammatory bowel disease), central nervous system (CNS) disorders suchas Parkinson's disease and Alzheimer's disease, headache, anxiety,multiple sclerosis, attenuation of morphine withdrawal, cardiovascularchanges, oedema, chronic inflammatory diseases such as rheumatoidarthritis, asthma/bronchial hyperreactivity and other respiratorydiseases including allergic rhinitis, inflammatory diseases of the gutincluding ulcerative colitis and Crohn's disease, ocular injury andocular inflammatory diseases. The background even mentions motionsickness and vomiting, but fails to call out nausea specifically.

Accordingly, there is a need in the art for more effective treatments ofnausea and vomiting, particularly nausea and vomiting emanating fromchemotherapy, radiotherapy and surgery. In addition, given the prolongedincidence of nausea and vomiting induced by these emetic events, thereis a need for treating such nausea and vomiting for a prolonged periodof time. Further, there is a need for the development of dosage forms toreduce drug-drug interaction, improve stability, and potentiate effectsof each component of the combined dosage forms.

OBJECTS OF THE INVENTION

Accordingly, it is an object of the invention to provide new methods fortreating or preventing nausea and vomiting using an NK₁ antagonist,particularly netupitant.

It is another object of the invention to provide methods for treating orpreventing nausea and vomiting in patients undergoing chemotherapy,radiotherapy, or surgery.

Still another object of the invention is to augment existing treatmentsfor CINV, RINV or PONV by steroids and 5-HT₃ antagonists, and therebyprovide additional protection against both nausea and vomiting,especially during the acute and delayed phases.

Another object of the invention is to provide a single combined dose ofnetupitant and a 5-HT₃ antagonist and to the use of that single dosewithout further dosing, for the treatment of nausea and vomiting duringthe acute and delayed phases of CINV, RINV or PONV.

It is another object to provide novel methods to treat nausea, vomiting,and other undesirable effects from moderately emetogenic and highlyemetogenic chemotherapy (“MEC and HEC”), especially HEC, during theacute and delayed phases following such treatments.

It is another object to provide novel dosage forms to reduce drug-druginteraction, improve stability, enhance bioavailability and potentiatetherapeutic effect of each component of the combined dosage formscomprising netupitant and/or 5-HT₃ antagonist and/or dexamethasone, intreating or preventing nausea and vomiting.

SUMMARY OF THE INVENTION

After extensive testing into the clinical effects of netupitant, it hasunexpectedly been discovered that netupitant is active against nausea,and that a single dose of netupitant is able to treat nausea andvomiting in response to highly and moderately emetogenic chemotherapyfor five consecutive days. It has also been discovered, quiteunexpectedly, that netupitant exhibits unique binding habits to NK₁receptors in the brain. In particular, it has been discovered thatnetupitant binds to NK₁ receptors in the striatum in a long-lastingmanner, and that less than 20 or 30% of netupitant is released fromstriatum NK₁ receptors even ninety-six hours after administration. Thisis in stark contrast to aprepitant, in which receptor binding dropsswiftly over time, and must be dosed repeatedly if emesis control isdesired throughout the delayed phase; and which shows no meaningfuleffect against nausea.

These discoveries have led to the development of a unique dosing regimento treat nausea during the first day after an emesis-inducing event, inaddition to the second, third, fourth and fifth days after suchinduction. Therefore, in one embodiment the invention provides a methodof treating nausea and vomiting for a period of five consecutive days ina patient in need thereof, comprising administering to said patientnetupitant or a pharmaceutically acceptable salt thereof in an amountwhich is therapeutically effective against nausea and vomiting duringthe acute and delayed phases, and which is effective to enter thesystemic circulation, cross the blood brain barrier and occupy at least70% of NK₁ receptors in the striatum seventy-two hours after saidadministration.

In another embodiment, the netupitant is combined with other anti-emeticagents, including a 5-HT₃ antagonist such as palonosetron and acorticosteroid such as dexamethasone, in a manner that results in evengreater efficacy against nausea. It has been discovered thatpalonosetron is much more effective in combinations with netupitant thanit is in combination with aprepitant, as reported by Grunberg et al.,Support Cancer Care (2009) 17:589-594. In addition, palonosetron showsan improved pharmacokinetic profile (e.g., better bioavailability) whenpalonosetron is in combination with netupitant as opposed topalonosetron in single dose administration. Based on these discoveries,solid oral dosage forms have been developed that combine netupitant oranother NK1 antagonist and palonosetron for the treatment of acute anddelayed emesis.

It has also been discovered that netupitant potentiates the effect ofdexamethasone, such that the dexamethasone is effective even whenadministered at sub-therapeutic doses (i.e. doses at which thedexamethasone would be ineffective if administered by itself).Therefore, in another embodiment the invention provides a combinationtherapy for treating nausea and vomiting for five consecutive days in apatient in need thereof, consisting essentially of:

-   -   Day 1 netupitant—administering to said patient on day one        netupinant or a pharmaceutically acceptable salt thereof, in an        amount which is therapeutically effective against nausea and        vomiting during the acute and delayed phases, and which is        effective to enter the systemic circulation, cross the blood        brain barrier and occupy at least 70% of NK₁ receptors in the        striatum seventy-two hours after said administration;    -   Day 1 palonosetron—administering to said patient on day one a        therapeutically effective amount of a 5-HT₃ antagonist        (preferably palonosetron) effective to treat said nausea and        vomiting during the acute and delayed phases;    -   Day 1 dexamethasone—administering to said patient on day one a        first dose of dexamethasone which is ineffective against nausea        and vomiting when administered alone, but effective against        nausea and vomiting when administered in combination with said        netupitant and palonosetron, wherein said first dose comprises        from 50 to 70% of a minimum effective dose when administered        alone; and    -   Days 2-5 dexamethasone—when the patient is undergoing highly        emetogenic chemotherapy, administering to said patient, on days        two, three and four, a second dose of dexamethasone which is        ineffective against nausea and vomiting when administered alone,        but effective against nausea and vomiting when administered in        combination with said netupitant, wherein said second dose        comprises from 40 to 60% of a minimum effective dose when        administered alone on days two, three and four.

The dosage forms are extremely versatile and stable owing to theirunique design and formulation. This versatility and stability isaccomplished by formulating the NK1 antagonist and palonosetron inseparate dosage forms and combining the dosage forms in one capsule.Thus, for example, the palonosetron can be formulated in a small gel-capat a dose of around 0.5 mg, and the netupitant or other NK1 antagonistformulated in a tablet at a dose of about 100 to 150 mg. A capsule canthen be filled with one or more palonosetron gel-caps and one or morenetupitant (or other NK1 antagonist) tablets, depending on thetherapeutic objective for the product. Because the palonosetron and NK1antagonist are in separate dosage units, they can be formulated withoutregard to the stability of the other, and without degradation toby-products, for instance(3S)-3-[(3aS)-1-oxo-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinoline-2-yl]-1-azoniabicyclo[2.2.2]octan-1-olate,a degradation by-product of palonosetron. As a result, the presentlydiscovered dosage forms offer advantages, such as, reducing drug-druginteraction, improving stability, and potentiating effects of eachcomponent of the dosage forms in treating or preventing emesis.

Thus, in one embodiment the invention provides an orally administereddosage form comprising a combination of palonosetron and an NK1antagonist (preferably netupitant), or a pharmaceutically acceptablesalt or prodrug thereof.

In another embodiment the invention provides an orally administeredcapsule dosage form comprising (a) an outer shell; (b) one or moretablets housed within said outer shell, each comprising an NK1antagonist (preferably netupitant) or a pharmaceutically acceptable saltor prodrug thereof and one or more pharmaceutically acceptableexcipients; and (c) one or more soft-gel capsules housed within theouter shell, each comprising palonosetron or a pharmaceuticallyacceptable ester or prodrug thereof and one or more pharmaceuticallyacceptable excipients; wherein said dosage form comprises(3S)-3-[(3aS)-1-oxo-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinoline-2-yl]-1-azoniabicyclo[2.2.2]octan-1-olatein an amount that does not exceed 3 wt. %.

In still other embodiments the invention provides methods of treatingacute and delayed-onset emesis by administering the dosage forms of thepresent invention to a human in need thereof, preferably shortly beforethe emesis inducing event.

Additional embodiments and advantages of the invention will be set forthin part in the description which follows, and in part will be obviousfrom the description, or may be learned by practice of the invention.The embodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims. It is to be understood that both theforegoing general description and the following detailed description areexemplary and explanatory only and are not restrictive of the invention,as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description, serve to explain theprinciples of the invention.

FIG. 1 depicts a capsule containing one soft-gel capsule of palonosetronand three tablets of netupitant.

FIG. 2 is a two dimensional graph plotting the pharmacokinetic profileof netupitant in humans following oral administration of netupitantalone and netupitant together with palonosetron.

FIG. 3 is a two dimensional graph plotting the pharmacokinetic profileof palonosetron in humans following oral administration of palonosetronalone and palonosetron together with netupitant.

FIG. 4 is a two dimensional graph plotting mean plasma concentrations ofdexamethasone over time following administration with and withoutnetupitant.

FIG. 5 contains two bar graphs that depict the average NK₁ receptoroccupancy at 6, 24, 48, 72 and 96 hours after a single oral dose of 100,300 and 450 mg. netupitant (N=2 for each dose) in striatum and occipitalcortex, as measured using positron emission topography.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing definitions and detailed description of preferred embodimentsof the invention and the non-limiting Examples included therein.

Definitions and Use of Terms

When the singular forms “a,” “an” and “the” or like terms are usedherein, they will be understood to include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “apharmaceutical carrier” includes mixtures of two or more such carriers,and the like. The word “or” or like terms as used herein means any onemember of a particular list and also includes any combination of membersof that list.

When used herein the term “about” or “ca.” will compensate forvariability allowed for in the pharmaceutical industry and inherent inpharmaceutical products, such as differences in product strength andbioavailability due to manufacturing variations and time-induced productdegradation. The term allows for any variation which in the practice ofpharmaceuticals would allow the product being evaluated to be consideredpharmaceutically equivalent or bioequivalent, or both if the contextrequires, to the recited strength of a claimed product.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.

As used herein, the term “Pharmaceutically acceptable” means that whichis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary use as well as humanpharmaceutical use. In addition, the term “pharmaceutically acceptablesalt” refers to a salt of a compound to be administered prepared frompharmaceutically acceptable non-toxic acids. Examples of suitableinorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,sulfuric, and phosphoric. Suitable organic acids may be selected fromaliphatic, aromatic, carboxylic and sulfonic classes of organic acids,examples of which are formic, acetic, propionic, succinic,camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic,mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic,furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic,galacturonic, and the like.

Pharmaceutically acceptable salts of palonosetron include palonosetronhydrochloride. Pharmaceutically acceptable pro-drugs of netupitantinclude those described in U.S. Pat. Nos. 6,593,472, 6,747,026 and6,806,370, including the N-oxide of netupitant. The contents of thesepublications are incorporated herein by reference. When a molecule isreferred to herein in its base or salt form, it will be understand alsoto encompass other pharmaceutically acceptable salt forms of themolecule.

As used herein, “therapeutically effective amount” refers to an amountsufficient to elicit the desired biological response. Thetherapeutically effective amount or dose will depend on the age, sex andweight of the patient, and the current medical condition of the patient.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors in addition to the presentdisclosure.

The minimum effective dose of dexamethasone, when used to treat CINVinduced by highly emetogenic chemotherapy, has been demonstrated to be20 mg. administered orally or by injection on day one, and sixteen mg.administered orally or by injection on days two, three and four. Jordanet al., THE ONCOLOGIST, Vol. 12, No. 9, 1143-1150, September 2007. Whenused to treat CINV induced by moderately emetogenic chemotherapy, theminimum effective dose of dexamethasone is 20 mg. administered orally orby injection on day one, and zero mg. on days two, three and four.

The terms “treating” and “treatment,” when used herein, refer to themedical management of a patient with the intent to cure, ameliorate,stabilize, or prevent a disease, pathological condition, or disorder.This term includes active treatment, that is, treatment directedspecifically toward the improvement of a disease, pathologicalcondition, or disorder, and also includes causal treatment, that is,treatment directed toward removal of the cause of the associateddisease, pathological condition, or disorder. In addition, this termincludes palliative treatment, that is, treatment designed for therelief of symptoms rather than the curing of the disease, pathologicalcondition, or disorder; preventative treatment, that is, treatmentdirected to minimizing or partially or completely inhibiting thedevelopment of the associated disease, pathological condition, ordisorder; and supportive treatment, that is, treatment employed tosupplement another specific therapy directed toward the improvement ofthe associated disease, pathological condition, or disorder.

As used herein, the term “significantly” refers to a level ofstatistical significance. The level of statistical significant can be,for example, of at least p<0.05, of at least p<0.01, of at leastp<0.005, or of at least p<0.001. Unless otherwise specified, the levelof statistical significance is p<0.05. When a measurable result oreffect is expressed or identified herein, it will be understood that theresult or effect is evaluated based upon its statistical significancerelative to a baseline. In like manner, when a treatment is describedherein, it will be understood that the treatment shows efficacy to adegree of statistical significance.

5-HT₃ antagonists include the various setrons such as, for example,palonosetron, ondansetron, dolasetron, tropisetron, and granisetron, andtheir pharmaceutically acceptable salts. A preferred 5-HT₃ antagonist ispalonosetron, especially its hydrochloride salt.

“Highly emetogenic chemotherapy” refers to chemotherapy having a highdegree of emetogenic potential, and includes chemotherapy based oncarmustine, cisplatin, cyclophosphamide≧1500 mg/m², dacarbazine,dactinomycin, mechlorethamine, and streptozotocin.

“Moderately emetogenic chemotherapy” refers to chemotherapy having amoderate degree of emetogenic potential, and includes chemotherapy basedon carboplatin, cyclophosphamide<1500 mg/m², cytarabine>1 mg/m²,daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide,irinotecan, and oxaliplatin.

Acute emesis refers to the first twenty-four hour period following anemesis-inducing event. Delayed emesis refers to the second, third,fourth and fifth twenty-four hour periods following an emesis-inducingevent. When a treatment is said to be effective during the delayedphase, it will be understood to mean that the effectiveness of thetreatment is statistically significant during the entire delayed phase,regardless of whether the treatment is effective during any particulartwenty-four hour period of the delayed phase. It will also be understoodthat the method can be defined based upon its effectiveness during anyone of the twenty-four hour periods of the delayed phase. Thus, unlessotherwise specified, any of the methods of treating nausea and/orvomiting during the delayed phases, as described herein, could also bepracticed to treat nausea and/or vomiting during the second, third,fourth or fifth twenty-four hour periods following an emesis inducingevent, or an combination thereof.

When ranges are given by specifying the lower end of a range separatelyfrom the upper end of the range, it will be understood that the rangecan be defined by selectively combining any one of the lower endvariables with any one of the upper end variables that is mathematicallypossible.

Methods of Treatment

As noted above, the invention is premised on several unique discoveries,and provides the following independent methods that can be practicedaccording to the present invention, including:

In a first principal embodiment, the invention provides a method oftreating nausea and vomiting for a period of five consecutive days in apatient in need thereof, comprising administering to said patientnetupitant or a pharmaceutically acceptable salt thereof in an amountwhich is therapeutically effective to treat nausea and vomiting duringthe acute and delayed phases, which enters the systemic circulation,crosses the blood brain barrier and occupies at least 70% of NK₁receptors in the striatum seventy-two hours after said administration.

In a second principal embodiment, the invention provides a combinationtherapy for treating nausea and vomiting for five consecutive days in apatient in need thereof, comprising:

(i) administering to said patient on day one netupitant or apharmaceutically acceptable salt thereof, in an amount which istherapeutically effective to treat nausea and vomiting during the acuteand delayed phases, which enters the systemic circulation, crosses theblood brain barrier and occupies at least 70% of NK₁ receptors in thestriatum seventy-two hours after said administration;

(ii) administering to said patient on day one a therapeuticallyeffective amount of a 5-HT₃ antagonist (preferably palonosetron, morepreferably 0.5 mg. of oral palonosetron as palonosetron hydrochloride)effective to treat said nausea and vomiting during the acute and delayedphases;

(iii) administering to said patient on day one a first dose ofdexamethasone which is ineffective against nausea and vomiting whenadministered alone, but effective against nausea and vomiting whenadministered in combination with said netupitant and palonosetron,wherein said first dose comprises from 50 to 70% of a minimum effectivedose when administered alone; and

(iv) if the patient is undergoing highly emetogenic chemotherapy,administering to said patient, on days two, three and four, a seconddose of dexamethasone which is ineffective against nausea and vomitingwhen administered alone, but effective against nausea and vomiting whenadministered in combination with said netupitant, wherein said seconddose comprises from 40 to 60% of a minimum effective dose whenadministered alone on days two, three and four.

Various sub-embodiments are envisaged for these principal embodiments.For example, the netupitant can be administered as a free base or apharmaceutically acceptable salt thereof, but is preferably administeredas the free base. In addition, the netupitant is preferably administeredin an amount ranging from about 50 to about 500 mg., from about 200 toabout 400 mg., and preferably about 300 mg., based on the weight of thefree base. A preferred route of administration for the netupitant isoral. In terms of binding to NK₁ receptors, the netupitant preferablybinds to at least 80 or even 85% of NK₁ receptors in the striatumseventy-two hours after administration. As of ninety six hours afteradministration, the netupitant preferably binds less than 70, 60, 50 oreven 40% of said NK₁ receptors.

The methods of the present invention are all effective at treating orpreventing nausea and vomiting induced by numerous events, includingchemotherapy induced nausea and vomiting (“CINV”), from moderately orhighly emetogenic chemotherapy, radiation therapy induced nausea andvomiting (“RINV”), and post-operative nausea and vomiting (“PONV”). Themethod is preferably performed shortly before the emesis inducing event(i.e. no more than 1 or 2 hours before the event). The methods may beused to treat nausea and vomiting during the acute phase of emesis, orduring the delayed phase.

The drugs specified by the individual embodiments may be administered byany suitable dosing regimen, as is well known in the art, but in apreferred embodiment the netupitant, 5-HT₃ antagonist and steroid areadministered orally. A preferred oral dose of palonosetron ranges fromabout 0.075 to about 1.0 mg, or from about 0.25 to about 0.75 mg, but ispreferably about 0.5 mg. A preferred oral dose of netupitant ranges fromabout 50 to 500 mg, or from about 200 to about 400 mg, but is preferablyabout 300 mg. A preferred dose of corticosteroid, preferablydexamethasone, is 12 mg administered orally or via injection on thefirst day of treatment, and 8 mg administered orally or via injection onthe second, third and fourth days after said treatment.

It will be further understood that the netupitant can be administered inprodrug form, in which case the invention will provide a method oftreatment by inducing plasma levels of netupitant, and in each case theplasma level of netupitant induced by the prodrug administration willcorrespond to the level attained by the administration of netupitant orits pharmaceutically acceptable salt, in the doses and routes ofadministration described herein.

Pharmaceutical Compositions

Various pharmaceutical compositions can be developed that make use ofthe combinations described herein. The composition can be administeredby any appropriate route, for example, orally, parenterally, orintravenously, in liquid or solid form.

Preferred modes of administrations of the active compounds areinjectable and/or oral. These compositions will generally include aninert diluent or an edible carrier. They may be enclosed in gelatincapsules (for oral use) or compressed into tablets (for oral or buccaluse) or formulated into troches (for buccal use). For these purposes,the active compound can be incorporated with excipients and used in theform of tablets, troches, or capsules. Pharmaceutically compatiblebinding agents, and/or adjuvant materials can be included as part of thecomposition.

Tablets, pills, capsules, troches and the like can contain any of thefollowing ingredients, or compounds of a similar nature: a binder suchas microcrystalline cellulose, gum tragacanth or gelatin; an excipientsuch as starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a gliding such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or otherenteric agents.

The compounds can be administered as a component of an elixir,suspension, syrup, wafer, orally disintegrating film, orallydisintegrating tablet, chewing gum or the like. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors.

Solutions or suspensions used for injection can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride, mannitol and dextrose.An injectable preparation can be enclosed in ampoules, disposablesyringes or multiple dose vials made of glass or plastic.

Combined Oral Dosage Forms

As discussed above, the invention provides versatile combined oraldosage forms of palonosetron and an NK1 antagonist that can be readilymodified depending on the therapeutic objective, and that do not presentissues of stability and degradation. In a preferred embodiment, theinvention provides a capsule for oral administration made from a hardouter shell that houses one or more NK1 antagonist tablets and one ormore palonosetron soft-gel capsules. The finished capsule and thetablet(s) and soft-gel capsule(s) housed within the capsule shell areall preferably formulated as immediate release dosage forms. Netupitantand casopitant, and their pharmaceutically acceptable salts, areparticularly preferred NK1 antagonists for the combined oral dosageforms of this invention.

While the NK1 antagonist is preferably formulated in a solid tablet, itwill be understood that it can be formulated in any solid form that issuitable for oral administration including, for example, a tablet orcapsule (hard or soft-gel). In a preferred embodiment, the NK1antagonist is formulated in a tablet. The number of NK1 antagonist unitscontained within the combined dosage form can be, for example, from 1 to10, 1 to 5, or 1 to 3. The netupitant units within the combined dosageform can provide anywhere from 50 to 500 mg of netupitant on anaggregate basis, preferably from 100 to 350 mg. Each netupitant unitpreferably comprises from 50 to 200 mg of netupitant, more preferably100 to 150 mg of netupitant, and most preferably 100 or 150 mg ofnetupitant.

The palonosetron can also be formulated in any solid form that issuitable for oral administration, although it is preferably formulatedas a soft-gel capsule. Non-limiting examples of suitable palonosetronsoft-gel capsules are provided in PCT publication WO 2008/049552, thecontents of which are hereby incorporated by reference. The number ofpalonosetron units within the combined dosage from can be, for example,from 1 to 5, from 1 to 3 or just 1. Each of the palonosetron unitswithin the combined dosage form can provide anywhere from 0.01 to 5.0 mgpalonosetron, preferably from 0.1 to 1.0 mg palonosetron on an aggregatebasis. Each palonosetron unit will preferably comprise from 0.1 to 1.0mg of palonosetron, most preferably about 0.25, 0.5, 0.75 or 1.0 mg ofpalonosetron.

FIG. 1 illustrates an exemplary embodiment of a combined oral dosageform of palonosetron and netupitant. The dosage form 10 comprises a twopiece hard outer shell that includes a body 20 and a cap 22. The dosageform 10 contains one palonosetron soft-gel capsule 30 (preferablycontaining 0.5 mg of palonosetron) and three netupitant tablets 40 (eachpreferably containing 100 mg of netupitant).

Hard Outer Shell

The hard outer shell of the present invention can be made of anypharmaceutically acceptable material that dissolves in gastric fluids.Preferred materials for the hard outer shell include, for example,gelatin, cellulose, starch, or hydroxypropyl methylcellulose (HPMC). Ina particular embodiment of the invention, the hard outer shell has amaximum oxygen permeability. Preferably, the oxygen permeability is lessabout 1.0×10⁻³, 5.0×10⁻⁴, 1.0×10⁻⁴, 5.0×10⁻⁵, or even 2.0×10⁻⁵ml·cm/(cm²·24 hr. atm).

The hard outer shell can be a continuous structure. Alternatively, thehard outer shell can be a two-piece hard capsule.

Soft-Gel Capsule

The soft-gel capsule used for the palonosetron preferably comprises asoft outer shell and a liquid inner fill composition comprisingpalonosetron hydrochloride. Non-limiting examples of suitablepalonosetron soft-gel capsules are provided in PCT publication WO2008/049552, the contents of which are hereby incorporated by reference.

The soft outer shell of the soft-gel capsule can contain any type ofmaterial that dissolves in gastric fluids. Preferred materials for thesoft outer shell include, for example, gelatin, cellulose, starch, orhydroxypropyl methylcellulose (HPMC). The soft-gel capsule can furthercomprise shell excipients such as glycerin, sorbitol, andcolorants/opacifers such as titanium dioxide. The soft-gel capsule canfurther include solvents such as purified water. In particularembodiments of the invention, the outer shell has a maximum oxygenpermeability, preferably of no more than 1.0×10⁻³, 5.0×10⁻⁴, 1.0×10⁻⁴,5.0×10⁻⁵, or even 2.0×10⁻⁵ ml·cm/(cm²·24 hr. atm). Suitable soft-gelcapsules include the 1.5-oval gelatine capsule shell manufactured byCatalent Pharma Solutions.

The liquid fill is preferably composed predominantly of one or morelipophilic components in an amount of from 50 wt. % to 99 wt. %,preferably from 75 wt. % to 98 wt. %. Preferred lipophilic componentsinclude, for example, mono- and di-glycerides of fatty acids, especiallyincluding the mono- and di-glycerides of capryl/capric acid. The liquidfill may also contain glycerin, preferably in an amount of from 1 to 15wt. %, more preferably from 2 to 10 wt. %. In one preferred embodiment,both the shell and the inner fill composition comprise glycerin. Inanother preferred embodiment, the liquid fill comprises about 0.25,0.50, 0.75 mg., or more of palonosetron as palonosetron hydrochloride.

The fill composition may comprise various means to facilitate thetransition of palonosetron from the dosage form to the gastrointestinalfluids of the GI tract, so that the palonosetron may be more readilyabsorbed into the bloodstream. For example, the liquid fill compositionmay contain a surfactant, optimally in an amount of from 0.1 wt. % to 6wt. %, from 0.5 wt. % to 5 wt. %, or from 1.0 wt. % to 3.0 wt. %. Theliquid fill composition preferably comprises greater than 0.1, 0.5, or1.0 wt. % of surfactant, and less than 10, 8, 5, 4, or even 4 wt. % ofsurfactant. A particularly preferred surfactant is polyglyceryl oleate.

Alternatively or in addition, the transitioning means for a liquidfilled capsule may comprise water that forms a single phase ormicroemulsion with the other liquid ingredients in the excipient base.The liquid fill composition preferably comprises from 0.05 wt. % to 30wt. % water, from 1 wt. % to 20 wt. % water, or from 2 wt. % to10 wt. %water. The liquid fill preferably comprises greater than 0.1, 0.5 or 1.0wt. % water, and less than 20, 15, 10, 8 or 5 wt. % water.

The active agent, which is preferably palonosetron hydrochloride, ispreferably present in the fill composition in an amount ranging from0.01 to 10.0 wt. %, from 0.05 to 5.0 wt. %, or from 0.1 wt. % to 2.0 wt.%. Alternatively, particularly stable formulations have been found wherethe concentration of palonosetron exceeds 0.3%, preferably at aconcentration no greater than 1 wt. %.

Tablet

The tablets of the present invention can include from 20 to 95 wt. % ofNK1 antagonist (preferably netupitant), and preferably comprises from 60to 80 wt. % of netupitant. In addition, the tablets can containdiluents, disintegrants, surfactants, binders, glidants, and/orlubricants. In a particular embodiment, the tablet comprises from 5 to25 wt. % of microcrystalline cellulose. The microcrystalline cellulosecan function as a diluent and disintegrant, and preferably comprises 15wt. % of the tablet. Another suitable disintegrant is sodiumcroscaramellose, which can be present in the tablet in an amount of from1 to 5 wt. %, preferably 2 wt. %.

A suitable binder for use in the tablet is polyvinylpyrrolidone, whichcan be present in the tablet in an amount from 1 to 10 wt. % of thetablet, and preferably 5 wt. %. A suitable glidant for use in the tabletis colloidal silicon dioxide, which can be present in the tablet in anamount of 2 wt. %. Suitable lubricants for use in the tablet includesodium stearyl fumarate and magnesium stearate, which can be present inthe tablet in an amount of 0.7 wt. % and 0.35 wt. %, respectively.

Application of the Combined Oral Dosage Forms

The invention further provides a method of treating emesis comprisingorally administering to a patient suffering from emesis, or at risk forsuffering emesis, a dosage form of the present invention. In stillfurther embodiments, the invention provides methods of treating emesisby administering one or more of the dosage forms described herein. Thedosage form is preferably administered shortly before the emesisinducing event (i.e. no more than 2 hours before the event). The emesismay be acute phase emesis (i.e. emesis experienced within about 24 hoursof an emesis inducing event), or delayed emesis (i.e. emesis experiencedafter the acute phase, but within seven, six, five or four days of anemesis inducing event). The emesis may constitute chemotherapy inducednausea and vomiting (“CINV”), from moderately or highly emetogenicchemotherapy, radiation therapy induced nausea and vomiting (“RINV”), orpost-operative nausea and vomiting (“PONV”).

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds claimed herein are made and evaluated, and are intended to bepurely exemplary of the invention and are not intended to limit thescope of what the inventors regard as their invention. Efforts have beenmade to ensure accuracy with respect to numbers (e.g., amounts,temperature, etc.) but some errors and deviations should be accountedfor. Unless indicated otherwise, parts are parts by weight, temperatureis in ° C. or is at room temperature, and pressure is at or nearatmospheric.

Example 1 Preparation of Oral Dosage Form

In a preferred embodiment the combination is administered in a capsuleoral dosage form, wherein the capsule houses one or more soft-gelcapsules for the palonosetron and one or more hard tablets for thenetupitant. Table 1 below describes a representative formulation for asoft-gel capsule containing 0.5 mg of palonosetron, suitable forinclusion in such a hard outer shell.

TABLE 1 REPRESENTATIVE SOFT-GEL FORMULATION Approximate AmountIngredient (mg/Capsule) Function Fill Solution Palonosetron HCl 0.56¹Active Mono- and di-glycerides 62.19 Solvent vehicle of Capryl/CapricAcid (Capmul MCM) Glycerin, anhydrous, 3.37 Plasticizer USP/Ph EurPolyglyceryl oleate 0.87 Surfactant (Plurol Oleique CC 497) Purifiedwater, USP/Ph Eur 2.94 Co-solvent Butylated hydroxyanisole 0.07Antioxidant (BHA), NF/Ph Eur Nitrogen — Theoretical fill weight 70.00 mgGelatine Capsule Shell, 1.5-oval (Catalent Pharma Solutions)² Gelatine(type 195), — Shell NF/Ph Eur Sorbitol Special/Glycerin — PlasticizerBlend 50/50 Titanium dioxide, — Colorant/Opacifier USP/Ph Eur Purifiedwater, USP/Ph Eur — Solvent ¹Corresponds to 0.50 mg. free base²Quantitative composition of capsule shell is proprietary to CatalentPharma Solutions

Table 2 below describes a representative formulation for a tabletcontaining 100 mg. of netupitant, suitable for inclusion in a hardshell.

TABLE 2 REPRESENTATIVE TABLET FORMULATION Approximate Amount Ingredient(mg/Tablet) Function Netupitant, milled 100 Active Microcrystallinecellulose pH 101 20.5 Diluent and disintegrant Sucrose Lauric AcidEsters 10.0 Surfactant Polyvinilpyrrolidone K30 7.0 Binder Sodiumcroscaramellose 3.0 Disintegrant Colloidal Silicon Dioxide 3.0 GlidantSodium Stearyl Fumarate 1.0 Lubricant Magnesium Stearate 0.5 LubricantTotal weight 145 mg

Example 2 Pharmacokinetics of Combind Dosage Form

Objective

The effects of palonosetron on the pharmacokinetics (PK) of netupitantand the effects of netupitant on the PK of palonosetron were examined inhealthy volunteers.

Methods

A randomized, open, 3-way crossover study was conducted. Each subjectparticipated in 3 treatment periods, each lasting approximately 12 days(Day −1 to Day 11). The treatment periods were separated by wash-outperiods of no less than 14 days (between Day 1 of any 2 consecutivetreatment periods).

The following treatments were investigated:

Treatment A: oral netupitant 450 mg. administered as single dose ofthree 150 mg. capsules.

Treatment B: oral palonosetron 0.75 mg. and oral netupitant 450 mg.administered simultaneously as three capsules of 150 mg. netupitantfollowed by 1 capsule of 0.75 mg. palonosetron.

Treatment C: oral palonosetron 0.75 mg. administered as single dose asone 0.75 mg. capsule.

Doses were administered under fasting conditions. Subjects fastedover-night for approximately 10 hours. Water, however, was permitted upto 1 hour pre-dose. Food intake was permitted 4 hours post-dose, andwater was allowed ad libitum 1 hour post-dose.

Doses were administered with the subject in an upright position. Thesubjects remained in an upright position for 4 hours post-dose. Thecapsules were swallowed whole with 250 mL of room-temperature tap water.Repeated PK blood sampling (for netupitant and/or palonosetron) wasperformed.

Results

The primary PK variables assessed for netupitant and palonosetron werethe maximum plasma concentration observed (C_(max)), the area under theplasma concentration versus time curve from time zero to the lastquantifiable sampling time point (t) (AUC_(0-t)), and the area under theplasma concentration versus time curve from time zero to infinity(AUC_(0-inf)). The secondary PK variables assessed were the terminalelimination half-life (t_(1/2,z)), and the time at which the maximumplasma concentration was observed (t_(max)). Results are depicted inbelow Tables 3 and 4, as well as FIGS. 2 and 3.

TABLE 3 Summary of Netupitant Pharmacokinetic Parameters Palonosetron0.75 mg + Parameter Netupitant 450 mg Netupitant 450 mg AUC_(0-t) [h *μg/L] 22808 (7270) 22775 (10064) AUC_(0-inf) [h * μg/L] 25927 (10156)26241 (13219) C_(max) [μg/L]  650.2 (257.8)  659.7 (325.7) t_(max) (h)  4.50 (3.00; 24.00)   4.50 (3.00; 23.95) t_(1/2,z) (h)  71.81 (37.10;261.61)  78.31 (50.17; 196.13) Mean and SD are shown, except for t_(max)and t_(1/2), where median and range are shown.

As can be seen in Table 4 below, palonosetron shows a betterpharmacokinetic profile when combined with Netupitant as opposed toadministered as a single dose of palonosetron, for example, the greaterAUC, the larger C_(max), the shorter t_(max) (the median t_(max) was 0.5hour shorter after administration of palonosetron in combination withnetupitant), and the longer t_(1/2,z).

TABLE 4 Summary of Palonosetron Pharmacokinetic Parameters Palonosetron0.75 mg + Parameter Palonosetron 0.75 mg Netupitant 450 mg AUC_(0-t)[h * μg/L]  67415 (19554)  74230 (24866) AUC_(0-inf) [h * μg/L]  70813(20415)  77254 (25402) C_(max) [μg/L] 1638.4 (415.5) 1863.1 (487.1)t_(max) (h)  5.02 (4.00; 8.00)  4.50 (3.00; 6.02) t_(1/2,z) (h)  34.73(19.61; 70.46)  36.91 (20.23; 56.08) Mean and SD are shown, except fort_(max) and t_(1/2), where median and range are shown.

Example 3 Netupitant+Dexamethasone Drug Interaction Study

The effect of netupitant on orally administered dexamethasonepharmacokinetics was evaluated in this study. This was a randomized,open, 3-period crossover study utilizing an incomplete Latin Squaredesign where subjects were given dexamethasone alone, or oral Netupitant100 mg., 300 mg. or 450 mg. each given with dexamethasone. Netupitantwas given orally on Day 1 only. The dexamethasone regimen for eachtreatment was 20 mg. orally Day 1, followed by 8 mg. orally every 12hours from Day 2 through Day 4. Nineteen subjects (12 male and 7 female)completed the study (i.e., all 3 treatment periods).

Mean plasma concentrations of dexamethasone were higher whendexamethasone was co-administered with netupitant (FIG. 4). The increaseappeared to be dependant on the netupitant exposure.

The AUC₀₋₂₄ (Day 1) of dexamethasone increased 1.5, 1.7 and 1.8-foldwith co-administration of 100, 300 and 450 mg. netupitant, respectively.The AUC₂₄₋₃₆ (Day 2) of dexamethasone increased 2.1, 2.4 and 2.6-foldand AUC₈₄₋₁₀₈ and AUC_(84-inf) (Day 4) increased 1.7, 2.4 and 2.7-fold,with co-administration of 100, 300 and 450 mg. netupitant, respectively.Dexamethasone C_(max) on Day 1 was only slightly affected byco-administration of netupitant (1.1-fold increase duringco-administration with 100 and 300 mg. netupitant, respectively, and1.2-fold increase during co-administration with 450 mg. netupitant).C_(max) on Day 2 and Day 4 was increased approximately 1.7-fold insubjects administered netupitant. Dexamethasone C_(min) on Days 2-4 wasincreased approximately 2.8, 4.3 and 4.6-fold with co-administration of100, 300 and 450 mg. netupitant, respectively. This clearly shows thatthe co-administration of netupitant and dexamethasone enhances thebioavailability of dexamethasone and provides a better therapeuticwindow of dexamethasone.

Example 4 Netupitant Pet Receptor Occupancy Study

This was a randomized, open-label, positron emission tomography (PET)study using 11C-GR205171 as tracer in 6 healthy male volunteers (2 perdose level) receiving single doses of netupitant (100, 300 or 450 mg) toinvestigate the degree of occupancy of NK₁ receptors in human brain, andto determine the relationship between plasma concentration of netupitantand NK₁ receptor occupancy (RO).

The anticipated high NK₁-RO (90% or higher) close to the expectedC_(max) (6 hours post dose) was reached for striatum, occipital cortex,frontal cortex and anterior cingulate in 3 of 6 subjects of whom 1received 300 mg. and 2 received 450 mg. of netupitant as a single oraldose.

All doses showed a relatively long duration of blockade of NK₁ receptorsand the decline over time was dose dependent. In the 100 mg. dose group,4 of 6 regions still had a mean NK₁-RO over 70% at 96 hours post dose.In the highest dose group (450 mg), 5 of 6 regions had a mean NK₁-RO of80% or higher at 96 hours post dose. A comparison of the results for thedose groups (100 mg., 300 mg. and 450 mg) showed a consistent but smallincrease in NK₁-ROs with increasing netupitant dose. (FIG. 5)

Example 5 Clinical Efficacy Study

A phase 2 trial evaluated three single doses of netupitant combined withpalonosetron and dexamethasone compared to palonosetron alone anddexamethasone to obtain dose ranging information for netupitant usedwith oral palonosetron in the CINV patient population.

The objective of the study was to compare the efficacy and safety ofthree single oral doses of netupitant combined with oral palonosetronand given with dexamethasone, versus oral palonosetron-alone given withdexamethasone (without netupitant) for the prevention of highlyemetogenic chemotherapy (HEC)-induced nausea and vomiting. TheFDA-approved oral aprepitant regimen given with IV ondansetron anddexamethasone was included in the study as an active comparator forexploratory purposes. The FDA-approved oral palonosetron 0.5 mg. dosewas used in each applicable treatment group in this study.

This was a multicenter, randomized, double-blind, double-dummy, parallelgroup, stratified study. Eligible patients were randomized (stratifiedby gender) to one of the following treatment groups:

-   Group 1—0.5 mg. oral palonosetron on Day 1 (with an oral    dexamethasone standard regimen: 20 mg. on Day 1 and 8 mg. BID from    Day 2 through Day 4)-   Group 2—100 mg. oral netupitant plus 0.5 mg. oral palonosetron on    Day 1 (with an oral dexamethasone adjusted regimen*: 12 mg. on Day 1    and 8 mg. daily from Day 2 through Day 4)-   Group 3—200 mg. oral netupitant plus 0.5 mg. oral palonosetron on    Day 1 (with an oral dexamethasone adjusted regimen*: 12 mg. on Day 1    and 8 mg. daily from Day 2 to Day 4)-   Group 4—300 mg. oral netupitant plus 0.5 mg. oral palonosetron on    Day 1 (with dexamethasone adjusted regimen*: 12 mg. on Day 1 and 8    mg. daily from Day 2 to Day 4)

Group 5—125 mg. oral aprepitant plus IV ondansetron 32 mg. (both onDay 1) then 80 mg. oral aprepitant on Day 2 and Day 3, (all with an oraldexamethasone adjusted regimen: 12 mg. on Day 1 and 8 mg. daily from Day2 through Day 4)

In addition, a Group 6 was added to the analysis for comparativepurposes, based on the results reported by Grunberg et al., SupportCancer Care (2009) 17:589-594:

-   Group 6—285 mg. oral aprepitant plus 20 mg. oral dexamethasone plus    0.2 mg. palonosetron i.v. (all on Day 1) then 80 mg. oral aprepitant

The primary efficacy endpoint was the complete response rate (defined asno emetic episodes, no rescue medication) within 120 hours after thestart of the highly emetogenic chemotherapy administration. Secondaryefficacy endpoints were:

-   -   Complete response for the 0-24 hour interval (acute phase); and        for the 25-120 hour interval (delayed phase);    -   Complete protection (defined as no emesis, no rescue therapy, no        significant nausea); Total control (defined as no emesis, no        rescue therapy and no nausea); No nausea (maximum VAS<5 mm); No        significant nausea (maximum VAS<25 mm); No rescue medication; No        emesis. These endpoints were evaluated for the 0-120 hour        interval (overall), acute and delayed phase.    -   Time to first emetic episode, Time to first rescue medication,        Time to treatment failure (based on time to the first emetic        episode or time to the first rescue medication, whichever occurs        first);    -   Severity of nausea for the overall, acute and delayed phase;        Patient global satisfaction with anti-emetic therapy by means of        VAS for each 24 hour interval.

Complete response rates are summarized in Table 5. The percent ofpatients with complete response over 0-120 hours after start ofcisplatin administration was 76.5% in the palonosetron alone group and87.4%, 87.6%, and 89.6% in the netupitant 100 mg., 200 mg., and 300 mg.groups, respectively. Differences from palonosetron-alone were greaterthan 10% (10.9% to 13.2%). All doses of netupitant were statisticallysuperior to palonosetron alone (p-value=0.004 for the netupitant 300 mg.combination group).

TABLE 5 COMPLETE RESPONSE RATE FOR THE OVERALL, ACUTE AND DELAYED PHASE:MFAS Population Palo + Netu Palo + Netu Palo + Netu Aprepitant Paloalone 100 mg 200 mg 300 mg Regimen Efficacy endpoint (n = 136) (n = 135)(n = 137) (n = 135) (N = 134) CR, Overall Phase, 0-120 h Percent ofPatients 76.5 87.4 87.6 89.6 86.6 Difference from Palo alone (%) 10.911.1 13.2 10.1 p-value (*) 0.018 0.017 0.004 0.027 CR, Acute Phase, 0-24h Percent of Patients 89.7 93.3 92.7 98.5 94.8 Difference from Paloalone (%) 3.6 3.0 8.8 5.1 p-value (*) 0.278 0.383 0.007 0.114 CR,Delayed Phase, 25-120 h Percent of Patients 80.1 90.4 91.2 90.4 88.8Difference from Palo alone (%) 10.2 11.1 10.2 8.7 p-value (*) 0.0180.010 0.018 0.043 (*) p-value from logistic regression analysis,aprepitant p-value from post-hoc logistic regression analysis.

Table 6 summarizes results for main secondary endpoints. In the overallphase, 76.5% of patients in the palonosetron-alone group did notexperience emesis, while 87.4, 87.6, and 91.1% of patients did notexperience emesis in the netupitant 100 mg., 200 mg. and 300 mg.combination groups, respectively (p<0.05 for all doses).

TABLE 6 SUMMARY OF SECONDARY EFFICACY RESULTS: PERCENT OF PATIENTS, MFASPOPULATION Palo + Netu Palo + Netu Palo + Netu Aprepitant Palo + AprepPalo alone 100 mg 200 mg 300 mg Regimen 285 mg Efficacy endpoint (n =136) (n = 135) (n = 137) (n = 135) (N = 134) (N = 41)** No EmesisOverall 76.5 87.4* 87.6* 91.1* 87.3* Acute 89.7 93.3 92.7 98.5* 94.8Delayed 80.1 90.4* 91.2* 91.9* 89.6* No Rescue Overall 95.6 97.8 10098.5 97.8 Acute 97.8 99.3 100 100 100 Delayed 97.1 97.8 100 98.5 97.8 NoNausea Overall 50.7 54.8 62.0 61.5 58.2 32 Acute 75.0 72.6 77.4 80.077.6 59 Delayed 53.7 59.3 65.0 68.1* 60.4 41 No Significant NauseaOverall 79.4 80.0 86.1 89.6* 85.8 56 Acute 93.4 94.1 94.2 98.5* 94.0 79Delayed 80.9 81.5 89.8* 90.4* 88.1 59 Total Control Overall 50.0 54.861.3 59.3 56.0 Acute 71.3 71.9 76.6 80.0 74.6 Delayed 52.2 59.3 65.0*65.9* 58.2 Complete Protection Overall 69.9 76.3 80.3* 83.0* 78.4 51Acute 87.5 89.6 88.3 97.0* 89.6 76 Delayed 73.5 80.0 87.6* 84.4* 82.1 66*p-value < 0.05 compared with palonosetron-alone; aprepitant comparisonsp-values calculated by post-hoc analysis **As reported by Grunberg etal., Support Cancer Care (2009) 17: 589-594

Example 7 Comparative Results of Aprepitant Dosing Regimen

The following Table 8 reports the results observed for an aprepitantdosing regimen, as described in the FDA approved prescribing informationfor aprepitant, which demonstrates, among other things, that aprepitanthas no meaningful effect on nausea. Table 7 reports the dosing regimen:

TABLE 7 Treatment Regimen Day 1 Days 2 to 4 Aprepitant Aprepitant 125 mgPO Aprepitant 80 mg Dexamethasone 12 mg PO PO Daily (Days 2 andOndansetron 32 mg I.V. 3 only) Dexamethasone 8 mg PO Daily (morning)

TABLE 8 Percent of Patients Receiving Highly Emetogenic ChemotherapyResponding by Treatment Group and Phase for Study 1 - Cycle 1 AprepitantStandard Regimen Therapy ENDPOINTS (N = 260)^(†) % (N = 261)^(†) %p-Value PRIMARY ENDPOINT Complete Response Overall^(‡) 73 52 <0.001OTHER PRESPECIFIED ENDPOINTS Complete Response Acute phase^(§) 89 76<0.001 Delayed phase^(||) 75 56 <0.001 Complete Protection Overall 63 490.001 Acute phase 85 75 NS* Delayed phase 66 52 <0.001 No Emesia Overall78 55 <0.001 Acute phase 90 79 0.001 Delayed phase 81 59 <0.001 NoNausea Overall 48 44 NS** Delayed phase 51 48 NS** No Significant NauseaOverall 73 66 NS** Delayed phase 75 69 NS** ^(†)N: Number of patients(older than 18 years of age) who received cisplatin, study drug, and hadat least one post-treatment efficacy evaluation. ^(‡)Overall: 0 to 120hours post-cisplatin treatment. ^(§)Acute phase: 0 to 24 hourspost-cisplatin treatment. ^(||)Delayed phase: 25 to 120 hourspost-cisplatin treatment. *Not statistically significant when adjustedfor multiple comparisons.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations can be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

The invention claimed is:
 1. A method of treating both nausea andvomiting for five consecutive days in a patient in need thereof,comprising: a) administering to said patient on day one netupitant or apharmaceutically acceptable salt thereof, in a therapeutically effectiveamount which enters the systemic circulation, crosses the blood brainbarrier and occupies at least 70% of neurokinin-1 (NK₁) receptors in thestriatum seventy-two hours after said administration; b) administeringto said patient on day one a therapeutically effective amount ofpalonosetron or a pharmaceutically acceptable salt thereof; and c)administering to said patient on day one a first dose of dexamethasonewhich is ineffective against chemotherapy induced nausea and vomiting(CINV) when administered alone, but effective against CINV whenadministered in combination with said netupitant, wherein said firstdose of dexamethasone comprises from 50 to 70% of a minimum effectivedose when administered alone against CINV; steps a b and (c) areeffective to treat both nausea and vomiting during the period defined bydays one through five; and steps (a), (b) and (c) are effective to treatboth nausea and vomiting to a greater extent during the period definedby days one through five than steps (b) and (c) alone.
 2. The method ofclaim 1, further comprising: d) administering to said patient, on daystwo, three and four, a second dose of dexamethasone which is ineffectiveagainst vomiting when administered alone against vomiting, but effectiveagainst vomiting when administered in combination with steps (a) and(b), wherein said second dose comprises from 40 to 60% of a minimumeffective dose when administered alone against vomiting.
 3. The methodof claim 1 or 2, wherein said netupitant occupies at least 80% of NK₁receptors in the striatum seventy-two hours after said administration.4. The method of claim 1, wherein only one dose of netupitant or apharmaceutically acceptable salt thereof is administered during saidfive days.
 5. The method of claim 1, wherein only one dose of netupitantor a pharmaceutically acceptable salt thereof is administered duringsaid five days, and said one dose is administered orally.
 6. The methodof claim 1, wherein said therapeutically effective amount of netupitantcomprises from about 200 to about 400 mg of netupitant or apharmaceutically acceptable salt thereof.
 7. The method of claim 1,wherein said therapeutically effective amount of netupitant comprisesabout 300 mg of netupitant as a free base.
 8. The method of claim 1,wherein said therapeutically minimum effective dose of dexamethasonewhen administered alone comprises from about 16 mg to about 20 mg ofdexamethasone.
 9. The method of claim 1, wherein only one dose of saidpalonosetron or a pharmaceutically acceptable salt thereof isadministered during said five days.
 10. The method of claim 1, whereinsaid therapeutically effective amount of palonosetron orpharmaceutically acceptable salt thereof is from about 0.25 to about0.75 mg based on the weight of the free base.
 11. The method of claim 1,wherein said palonosetron is administered as palonosetron hydrochloride,and said therapeutically effective amount of said palonosetronhydrochloride is about 0.56 mg of palonosetron hydrochloride,corresponding to about 0.5 mg of palonosetron as a free base.
 12. Themethod of claim 1, wherein said palonosetron is administered orally. 13.The method of claim 1, comprising orally administering: a) about 300 mgof netupitant as a free base on day one; b) about 0.56 mg ofpalonosetron hydrochloride, corresponding to about 0.5 mg ofpalonosetron as a free base, on day one; and c) about 12 mg ofdexamethasone on day one.
 14. The method of claim 1, comprising orallyadministering: a) about 300 mg of netupitant as a free base on day one;b) about 0.56 mg of palonosetron hydrochloride (corresponding to about0.5 mg of palonosetron as a free base) on day one; c) about 12 mg ofdexamethasone on day one; and d) about 8 mg of dexamethasone on daystwo, three and four.
 15. The method of claim 1, wherein said nausea andvomiting is chemotherapy induced nausea and vomiting (“CINV”), radiationtherapy induced nausea and vomiting (“RINV”), or post-operative nauseaand vomiting (“PONV”).
 16. The method of claim 1, wherein said nauseaand vomiting is induced by moderately or highly emetogenic chemotherapy.17. The method of claim 1, comprising administering moderately or highlyemetogenic chemotherapy within from about one hour to about two hours ofsaid administration of said netupitant or pharmaceutically acceptablesalt thereof.
 18. The method of claim 1, comprising treating nausea andvomiting in response to highly emetogenic chemotherapy during the acutephase, or in response to highly emetogenic chemotherapy during thedelayed phase, or in response to moderately emetogenic chemotherapyduring the acute phase, or in response to moderately emetogenicchemotherapy during the delayed phase.
 19. A method of treating bothnausea and vomiting in a human subject in need thereof during the acuteor delayed phases of chemotherapy induced nausea and vomiting (CINV) inresponse to moderately or highly emetogenic chemotherapy, comprisingadministering to said subject before said chemotherapy a therapeuticallyeffective amount of netupitant or a pharmaceutically acceptable saltthereof and a therapeutically effective amount of palonosetron or apharmaceutically acceptable salt thereof.
 20. The method of claim 19,comprising orally administering from about 200 to about 400 mg ofnetupitant or a pharmaceutically acceptable salt thereof, and from about0.25 to about 0.75 mg of palonosetron or a pharmaceutically acceptablesalt thereof.
 21. The method of claim 19, comprising orallyadministering about 300 mg of netupitant as the free base and about 0.56mg of palonosetron hydrochloride.
 22. The method of claim 19, furthercomprising, if said patient is undergoing highly emetogenicchemotherapy, administering a sub-therapeutic dose of dexamethasone ondays one, two, three and four, wherein day one is the day on whichnetupitant and palonosetron, or pharmaceutically acceptable saltsthereof, are administered.
 23. The method of claim 19, furthercomprising, if said patient is undergoing highly emetogenicchemotherapy, orally administering 12 mg of dexamethasone on day one and8 mg of dexamethasone on days two, three and four, wherein day one isthe day on which netupitant and palonosetron, or pharmaceuticallyacceptable salts thereof, are administered.
 24. The method of claim 1,wherein said netupitant or pharmaceutically acceptable salt thereof andsaid palonosetron or pharmaceutically acceptable salt thereof aresynergistically effective to antagonize NK1 activity.
 25. The method ofclaim 19, wherein said netupitant or pharmaceutically acceptable saltthereof and said palonosetron or pharmaceutically acceptable saltthereof are synergistically effective to antagonize NK1 activity.